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Adaptations of leptin, ghrelin or insulin during weight loss as predictors of weight regain: a review of current literature

Abstract

Numerous laboratory studies involving both animal and human models indicate that weight loss induces changes in leptin, ghrelin and insulin sensitivity, which work to promote weight regain. It is unclear, however, whether these biological changes serve as a biomarker for predicting weight regain in free-living humans in which biological, behavioral and environmental factors are likely at play. We identified 12 studies published between January 1995 and December 2011 that reported changes in leptin, ghrelin or insulin during intentional weight loss with a follow-up period to assess regain. Two of the nine studies examining leptin suggested that larger decreases were associated with greater regain, three studies found the opposite (smaller decreases were associated with greater regain), whereas four studies found no significant relationship; none of the studies supported the hypothesis that increases in ghrelin during weight loss were associated with regain. One study suggested that improvements in insulin resistance were associated with weight gain, but five subsequent studies reported no association. Changes in leptin, ghrelin or insulin sensitivity, taken alone, are not sufficient to predict weight regain following weight loss in free-living humans. In future studies, it is important to include a combination of physiological, behavioral and environmental variables in order to identify subgroups at greatest risk of weight regain.

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References

  1. Flegal KM, Carroll MD, Ogden CL, Curtin LR . Prevalence and trends in obesity among US adults, 1999-2008. JAMA 2010; 303: 235–241.

    CAS  PubMed  Google Scholar 

  2. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 2006; 113: 898–918.

    Article  PubMed  Google Scholar 

  3. Kahn SE, Hull RL, Utzschneider KM . Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444: 840–846.

    Article  CAS  PubMed  Google Scholar 

  4. Pi-Sunyer X, Blackburn G, Brancati FL, Bray GA, Bright R, Clark JM et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes care 2007; 30: 1374–1383.

    Article  PubMed  Google Scholar 

  5. Van Gaal LF, Wauters MA, De Leeuw IH . The beneficial effects of modest weight loss on cardiovascular risk factors. Int J Obes Relat Metab Disord 1997; 21 (Suppl 1): S5–S9.

    PubMed  Google Scholar 

  6. Votruba SB, Blanc S, Schoeller DA . Pattern and cost of weight gain in previously obese women. Am J Physiol Endocrinol Metab 2002; 282: E923–E930.

    Article  CAS  PubMed  Google Scholar 

  7. Weiss EC, Galuska DA, Kettel Khan L, Gillespie C, Serdula MK . Weight regain in U.S. adults who experienced substantial weight loss, 1999-2002. Am J Prev Med 2007; 33: 34–40.

    Article  PubMed  Google Scholar 

  8. Field AE, Wing RR, Manson JE, Spiegelman DL, Willett WC . Relationship of a large weight loss to long-term weight change among young and middle-aged US women. Int J Obes Relat Metab Disord 2001; 25: 1113–1121.

    Article  CAS  PubMed  Google Scholar 

  9. Sarlio-Lahteenkorva S, Rissanen A, Kaprio J . A descriptive study of weight loss maintenance: 6 and 15 year follow-up of initially overweight adults. Int J Obes Relat Metab Disord 2000; 24: 116–125.

    Article  CAS  PubMed  Google Scholar 

  10. MacLean PS, Higgins JA, Johnson GC, Fleming-Elder BK, Donahoo WT, Melanson EL et al. Enhanced metabolic efficiency contributes to weight regain after weight loss in obesity-prone rats. Am J Physiol Regul Integr Comp Physiol 2004; 287: R1306–R1315.

    Article  CAS  PubMed  Google Scholar 

  11. MacLean PS, Higgins JA, Johnson GC, Fleming-Elder BK, Peters JC, Hill JO . Metabolic adjustments with the development, treatment, and recurrence of obesity in obesity-prone rats. Am J Physiol Regul Integr Comp Physiol 2004; 287: R288–R297.

    Article  CAS  PubMed  Google Scholar 

  12. MacLean PS, Higgins JA, Jackman MR, Johnson GC, Fleming-Elder BK, Wyatt HR et al. Peripheral metabolic responses to prolonged weight reduction that promote rapid, efficient regain in obesity-prone rats. Am J Physiol Regul Integr Comp Physiol 2006; 290: R1577–R1588.

    Article  CAS  PubMed  Google Scholar 

  13. Beck EJ, Tapsell LC, Batterham MJ, Tosh SM, Huang XF . Oat beta-glucan supplementation does not enhance the effectiveness of an energy-restricted diet in overweight women. Br J Nutr 2010; 103: 1212–1222.

    CAS  PubMed  Google Scholar 

  14. Capel F, Klimcakova E, Viguerie N, Roussel B, Vitkova M, Kovacikova M et al. Macrophages and adipocytes in human obesity: adipose tissue gene expression and insulin sensitivity during calorie restriction and weight stabilization. Diabetes 2009; 58: 1558–1567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Das SK, Gilhooly CH, Golden JK, Pittas AG, Fuss PJ, Cheatham RA et al. Long-term effects of 2 energy-restricted diets differing in glycemic load on dietary adherence, body composition, and metabolism in CALERIE: a 1-y randomized controlled trial. Am J Clin Nutr 2007; 85: 1023–1030.

    Article  CAS  PubMed  Google Scholar 

  16. de Luis DA, Sagrado MG, Conde R, Aller R, Izaola O . The effects of two different hypocaloric diets on glucagon-like peptide 1 in obese adults, relation with insulin response after weight loss. J Diab Complications 2009; 23: 239–243.

    Article  Google Scholar 

  17. Hayes MR, Miller CK, Ulbrecht JS, Mauger JL, Parker-Klees L, Gutschall MD et al. A carbohydrate-restricted diet alters gut peptides and adiposity signals in men and women with metabolic syndrome. J Nutr 2007; 137: 1944–1950.

    Article  CAS  PubMed  Google Scholar 

  18. Heini AF, Lara-Castro C, Kirk KA, Considine RV, Caro JF, Weinsier RL . Association of leptin and hunger-satiety ratings in obese women. Int J Obes Relat Metab Disord 1998; 22: 1084–1087.

    Article  CAS  PubMed  Google Scholar 

  19. Hietaniemi M, Jokela M, Rantala M, Ukkola O, Vuoristo JT, Ilves M et al. The effect of a short-term hypocaloric diet on liver gene expression and metabolic risk factors in obese women. Nutr Metab Cardiovasc Dis 2009; 19: 177–183.

    Article  CAS  PubMed  Google Scholar 

  20. Keim NL, Stern JS, Havel PJ . Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women. Am J Clin Nutr 1998; 68: 794–801.

    Article  CAS  PubMed  Google Scholar 

  21. Lien LF, Haqq AM, Arlotto M, Slentz CA, Muehlbauer MJ, McMahon RL et al. The STEDMAN project: biophysical, biochemical and metabolic effects of a behavioral weight loss intervention during weight loss, maintenance, and regain. OMICS 2009; 13: 21–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1: 1155–1161.

    Article  CAS  PubMed  Google Scholar 

  23. Olivan B, Teixeira J, Bose M, Bawa B, Chang T, Summe H et al. Effect of weight loss by diet or gastric bypass surgery on peptide YY3-36 levels. Ann Surg 2009; 249: 948–953.

    Article  PubMed  Google Scholar 

  24. Rosenbaum M, Nicolson M, Hirsch J, Murphy E, Chu F, Leibel RL . Effects of weight change on plasma leptin concentrations and energy expenditure. J Clin Endocrinol Metab 1997; 82: 3647–3654.

    CAS  PubMed  Google Scholar 

  25. Straznicky NE, Grima MT, Eikelis N, Nestel PJ, Dawood T, Schlaich MP et al. The effects of weight loss versus weight loss maintenance on sympathetic nervous system activity and metabolic syndrome components. J Clin Endocrinol Metab 2011; 96: E503–E508.

    Article  CAS  PubMed  Google Scholar 

  26. Verdich C, Toubro S, Buemann B, Lysgard Madsen J, Juul Holst J, Astrup A . The role of postprandial releases of insulin and incretin hormones in meal-induced satiety—effect of obesity and weight reduction. In J Obes Relat Metab Disord 2001; 25: 1206–1214.

    Article  CAS  Google Scholar 

  27. Jequier E . Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci 2002; 967: 379–388.

    Article  CAS  PubMed  Google Scholar 

  28. Levin BE, Keesey RE . Defense of differing body weight set points in diet-induced obese and resistant rats. Am J Physiol 1998; 274 (2 Pt 2): R412–R419.

    CAS  PubMed  Google Scholar 

  29. Lofgren P, Andersson I, Adolfsson B, Leijonhufvud BM, Hertel K, Hoffstedt J et al. Long-term prospective and controlled studies demonstrate adipose tissue hypercellularity and relative leptin deficiency in the postobese state. J Clin Endocrinol Metab 2005; 90: 6207–6213.

    Article  PubMed  Google Scholar 

  30. Maclean PS, Bergouignan A, Cornier MA, Jackman MR . Biology’s response to dieting: the impetus for weight regain. Am J Physiol Regul Integr Compar Physiol 2011; 301: R581–R600.

    Article  CAS  Google Scholar 

  31. Rosenbaum M, Sy M, Pavlovich K, Leibel RL, Hirsch J . Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. J Clin Invest 2008; 118: 2583–2591.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kissileff HR, Thornton JC, Torres MI, Pavlovich K, Mayer LS, Kalari V et al. Leptin reverses declines in satiation in weight-reduced obese humans. Am J Clin Nutr 2012; 95: 309–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002; 346: 1623–1630.

    Article  PubMed  Google Scholar 

  34. Hansen TK, Dall R, Hosoda H, Kojima M, Kangawa K, Christiansen JS et al. Weight loss increases circulating levels of ghrelin in human obesity. Clin Endocrinol 2002; 56: 203–206.

    Article  CAS  Google Scholar 

  35. Lejeune MP, Hukshorn CJ, Saris WH, Westerterp-Plantenga MS . Effects of very low calorie diet induced body weight loss with or without human pegylated recombinant leptin treatment on changes in ghrelin and adiponectin concentrations. Physiol Behav 2007; 91: 274–280.

    Article  CAS  PubMed  Google Scholar 

  36. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K . Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656–660.

    Article  CAS  PubMed  Google Scholar 

  37. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T et al. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 2000; 141: 4255–4261.

    Article  CAS  PubMed  Google Scholar 

  38. Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D . Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Am J Physiol Endocrinol Metab 2004; 287: E297–E304.

    Article  CAS  PubMed  Google Scholar 

  39. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001; 86: 5992.

    Article  CAS  PubMed  Google Scholar 

  40. Erez G, Tirosh A, Rudich A, Meiner V, Schwarzfuchs D, Sharon N et al. Phenotypic and genetic variation in leptin as determinants of weight regain. Int J Obes 2011; 35: 785–792.

    Article  CAS  Google Scholar 

  41. Soni AC, Conroy MB, Mackey RH, Kuller LH . Ghrelin, leptin, adiponectin, and insulin levels and concurrent and future weight change in overweight, postmenopausal women. Menopause 2011; 18: 296–301.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Torgerson JS, Carlsson B, Stenlof K, Carlsson LM, Bringman E, Sjostrom L . A low serum leptin level at baseline and a large early decline in leptin predict a large 1-year weight reduction in energy-restricted obese humans. J Clin Endocrinol Metab 1999; 84: 4197–4203.

    CAS  PubMed  Google Scholar 

  43. Crujeiras AB, Goyenechea E, Abete I, Lage M, Carreira MC, Martinez JA et al. Weight regain after a diet-induced loss is predicted by higher baseline leptin and lower ghrelin plasma levels. J Clin Endocrinol Metab 2010; 95: 5037–5044.

    Article  CAS  PubMed  Google Scholar 

  44. Mavri A, Stegnar M, Sabovic M . Do baseline serum leptin levels predict weight regain after dieting in obese women? Diab Obes Metab 2001; 3: 293–296.

    Article  CAS  Google Scholar 

  45. Wing RR, Sinha MK, Considine RV, Lang W, Caro JF . Relationship between weight loss maintenance and changes in serum leptin levels. Horm Metab Res 1996; 28: 698–703.

    Article  CAS  PubMed  Google Scholar 

  46. Vogels N, Westerterp-Plantenga MS . Successful long-term weight maintenance: a 2-year follow-up. Obesity 2007; 15: 1258–1266.

    Article  PubMed  Google Scholar 

  47. Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med 2011; 365: 1597–1604.

    Article  CAS  PubMed  Google Scholar 

  48. Wang P, Holst C, Andersen MR, Astrup A, Bouwman FG, van Otterdijk S et al. Blood profile of proteins and steroid hormones predicts weight change after weight loss with interactions of dietary protein level and glycemic index. PLoS ONE 2011; 6: 2.

    Article  CAS  Google Scholar 

  49. Garcia JM, Iyer D, Poston WS, Marcelli M, Reeves R, Foreyt J et al. Rise of plasma ghrelin with weight loss is not sustained during weight maintenance. Obesity 2006; 14: 1716–1723.

    Article  CAS  PubMed  Google Scholar 

  50. Goodpaster BH, Kelley DE, Wing RR, Meier A, Thaete FL . Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. Diabetes 1999; 48: 839–847.

    Article  CAS  PubMed  Google Scholar 

  51. Yost TJ, Jensen DR, Eckel RH . Weight regain following sustained weight reduction is predicted by relative insulin sensitivity. Obes Res 1995; 3: 583–587.

    Article  CAS  PubMed  Google Scholar 

  52. Wing RR . Insulin sensitivity as a predictor of weight regain. Obes Res 1997; 5: 24–29.

    Article  CAS  PubMed  Google Scholar 

  53. Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest 2005; 115: 3579–3586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cummings DE, Schwartz MW . Genetics and pathophysiology of human obesity. Ann Rev Med 2003; 54: 453–471.

    Article  CAS  PubMed  Google Scholar 

  55. Ahima RS, Antwi DA . Brain regulation of appetite and satiety. Endocrinol Metab Clin North Am 2008; 37: 811–823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Anderson JW, Konz EC, Frederich RC, Wood CL . Long-term weight-loss maintenance: a meta-analysis of US studies. Am J Clin Nutr 2001; 74: 579–584.

    Article  CAS  PubMed  Google Scholar 

  57. Shai I, Schwarzfuchs D, Henkin Y, Shahar DR, Witkow S, Greenberg I et al. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med 2008; 359: 229–241.

    Article  CAS  PubMed  Google Scholar 

  58. Nicklas BJ, Katzel LI, Ryan AS, Dennis KE, Goldberg AP . Gender differences in the response of plasma leptin concentrations to weight loss in obese older individuals. Obes Res 1997; 5: 62–68.

    Article  CAS  PubMed  Google Scholar 

  59. Clegg DJ, Brown LM, Woods SC, Benoit SC . Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes 2006; 55: 978–987.

    Article  CAS  PubMed  Google Scholar 

  60. Woods SC, Gotoh K, Clegg DJ . Gender differences in the control of energy homeostasis. Exp Biol Med (Maywood) 2003; 228: 1175–1180.

    Article  CAS  Google Scholar 

  61. Larsen LH, Angquist L, Vimaleswaran KS, Hager J, Viguerie N, Loos RJ et al. Analyses of single nucleotide polymorphisms in selected nutrient-sensitive genes in weight-regain prevention: the DIOGENES study. Am J Clin Nutr 2012; 95: 1254–1260.

    Article  CAS  PubMed  Google Scholar 

  62. Swinburn B, Egger G . The runaway weight gain train: too many accelerators, not enough brakes. BMJ 2004; 329: 736–739.

    Article  PubMed  PubMed Central  Google Scholar 

  63. McAllister EJ, Dhurandhar NV, Keith SW, Aronne LJ, Barger J, Baskin M et al. Ten putative contributors to the obesity epidemic. Crit Rev Food Sci Nutr 2009; 49: 868–913.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Hersoug LG, Sjodin A, Astrup A . A proposed potential role for increasing atmospheric CO2 as a promoter of weight gain and obesity. Nutr Diab 2012; 2: e31.

    Article  Google Scholar 

  65. Tremblay A, Pelletier C, Doucet E, Imbeault P . Thermogenesis and weight loss in obese individuals: a primary association with organochlorine pollution. Int J Obes Relat Metab Disord 2004; 28: 936–939.

    Article  CAS  PubMed  Google Scholar 

  66. Muller MJ, Bosy-Westphal A, Heymsfield SB . Is there evidence for a set point that regulates human body weight? F1000 Med Rep 2010; 2: 59.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Wing RR, Phelan S . Long-term weight loss maintenance. Am J Clin Nutr 2005; 82 (1 Suppl): 222S–225SS.

    Article  CAS  PubMed  Google Scholar 

  68. Wing RR, Papandonatos G, Fava JL, Gorin AA, Phelan S, McCaffery J et al. Maintaining large weight losses: the role of behavioral and psychological factors. J Consult Clin Psychol 2008; 76: 1015–1021.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Middleton KM, Patidar SM, Perri MG . The impact of extended care on the long-term maintenance of weight loss: a systematic review and meta-analysis. Obes Rev 2012; 13: 509–517.

    Article  PubMed  Google Scholar 

  70. Wadden TA, Considine RV, Foster GD, Anderson DA, Sarwer DB, Caro JS . Short- and long-term changes in serum leptin dieting obese women: effects of caloric restriction and weight loss. J Clin Endocrinol Metab 1998; 83: 214–218.

    CAS  PubMed  Google Scholar 

  71. Cummings DE, Shannon MH . Roles for ghrelin in the regulation of appetite and body weight. Arch Surg 2003; 138: 389–396.

    Article  CAS  PubMed  Google Scholar 

  72. Romon M, Lebel P, Fruchart JC, Dallongeville J . Postprandial leptin response to carbohydrate and fat meals in obese women. J Am Coll Nutr 2003; 22: 247–251.

    Article  PubMed  Google Scholar 

  73. le Roux CW, Patterson M, Vincent RP, Hunt C, Ghatei MA, Bloom SR . Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. J Clin Endocrinol Metab 2005; 90: 1068–1071.

    Article  CAS  PubMed  Google Scholar 

  74. Boule NG, Chaput JP, Doucet E, Richard D, Despres JP, Bouchard C et al. Glucose homeostasis predicts weight gain: prospective and clinical evidence. Diab Metab Res Rev 2008; 24: 123–129.

    Article  CAS  Google Scholar 

  75. Farooqi IS . Genetic, molecular and physiological insights into human obesity. Eur J Clin Invest 2011; 41: 451–455.

    Article  PubMed  Google Scholar 

  76. Sloth B, Due A, Larsen TM, Holst JJ, Heding A, Astrup A . The effect of a high-MUFA, low-glycaemic index diet and a low-fat diet on appetite and glucose metabolism during a 6-month weight maintenance period. Br J Nutr 2009; 101: 1846–1858.

    Article  CAS  PubMed  Google Scholar 

  77. MacLean PS, Higgins JA, Wyatt HR, Melanson EL, Johnson GC, Jackman MR et al. Regular exercise attenuates the metabolic drive to regain weight after long-term weight loss. Am J Physiol Regul Integr Comp Physiol 2009; 297: R793–R802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

KS was supported by a T32 Training Fellowship (Training in Behavioral and Preventive Medicine; T32 HL076134).

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Strohacker, K., McCaffery, J., MacLean, P. et al. Adaptations of leptin, ghrelin or insulin during weight loss as predictors of weight regain: a review of current literature. Int J Obes 38, 388–396 (2014). https://doi.org/10.1038/ijo.2013.118

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